Abstract

Human pluripotent stem cells (hPSCs) are powerful tools for modeling early human embryogenesis and provide a crucial source of differentiated cells for regenerative medicine. Maintaining their genetic stability is paramount for both basic research and clinical applications. However, it is now well-documented that hPSCs acquire non-random genetic changes upon culture. Some of the acquired genetic aberrations are associated with a selective growth advantage in variant hPSCs and are also linked to oncogenesis in other contexts. This raises significant concerns about their potential to confer tumorigenic or malignant properties on transplanted differentiated cells or any residual undifferentiated hPSCs. Furthermore, such genetic changes can undermine basic research by leading to unpredictable results in disease modeling and developmental studies due to aberrant proliferation rates or altered differentiation abilities.

In this talk, I will present our ongoing work focused on elucidating the molecular mechanisms that underpin the maintenance of hPSC genome integrity. I will discuss how disruptions to these mechanisms can lead to undesired genetic changes. Moreover, I will also share our findings demonstrating that the dominance of genetically variant hPSCs in mosaic cultures is significantly enhanced through competitive interactions, leading to the elimination of wild-type cells. Ultimately, our work is informing novel approaches to minimize the occurrence of genetic changes in hPSC cultures, ensuring their reliability for both clinical and research use.